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A 42-year-old female patient presented with pyelonephritis. Two days later she complained of hematomas and petechia of the extremities.Acquired thrombotic thrombocytopenic purpura was diagnosed. Laboratory result showed a thrombotic microangiopathy and thrombocytopenia of 8 × 10E9/l. ADAMTS13-activity was reported to be reduced and inhibitory antibodies to be present.The patient was placed on a therapy with plasma exchange, high-dose steroids, and caplacizumab based on a positive PLASMIC score. Once the diagnosis was confirmed by diminished ADAMTS13-activity and the presence of autoantibodies, rituximab was added. The patient responded well but showed persistently elevated levels of ADAMTS13-autoantibodies, which lead to an extension of Caplacizumab treatment to 58 days.Caplacizumab represents a novel effective treatment option for patients with acquired thrombocytopenic purpura. Time to treatment response as well as the risk of relapse were shown to be significantly reduced. However, persistent autoimmune activity can be demonstrated in a significant portion of the patients after the end of treatment putting them at risk for relapses. Thus, careful and frequent surveillance is required.Eine 42-jährige Patientin stellte sich zunächst mit einer Pyelonephritis vor. Zwei Tage später traten Hämatome und punktuelle Einblutungen der Extremitäten auf.Eine erworbene thrombotisch-thrombozytopenische Purpura wurde diagnostiziert. Der klinische Befund zeigte das Bild einer thrombotischen Mikroangiopathie mit einer Thrombopenie von 8 × 10E9/l. Es konnten eine erniedrigte ADAMTS13-Aktivität und Autoantikörper nachgewiesen werden.Bei positivem PLASMIC Score wurde vor Erhalt der ADAMTS13-Diagnostik eine Therapie mittels Plasmaseparation, Steroiden und Caplacizumab eingeleitet und im Verlauf um Rituximab ergänzt. Darunter kam es zu einer raschen klinischen Remission mit jedoch persistierenden ADAMTS13-Antikörpern und reduzierter -Aktivität, so dass Caplacizumab für insgesamt 58 Tage appliziert wurde.Mit Caplacizumab steht eine wirkungsvolle neue Therapie der erworbenen thrombotisch-thrombozytopenischen Purpura zur Verfügung. Die Zeit bis zum klinischen Ansprechen und die Zahl der Rückfälle können deutlich reduziert werden. Liegt jedoch eine persistierende Autoimmunaktivität über den Therapiezeitraum hinaus vor, geht diese mit einem hohen Rückfallrisiko einher und erfordert engmaschige Kontrollen.

We report on the case of a young women presenting with macrohaematuria, petechiae and strong headaches.Laboratory showed a thrombotic microangiopathy with helmet cells, increased LDH levels (600 U/l), and thrombocytopenia (40,000/μl).Due to strong haemolytic activity and headache with blurred vision, immediate plasma separation with fresh frozen plasma was commenced. Markedly decreased ADAMTS13 activity and detection of anti-ADAMTS13 antibodies were consistent with the diagnosis of idiopathic thrombotic thrombocytopenic purpura. In total, 11 plasma separations were required to stop disease activity. In parallel, immunosuppressive therapy using glucocorticoids was initiated. The patient was discharged from the hospital in a good general condition and with normalized laboratory findings 26 days after hospitalization.All patients with anemia and thrombocytopenia should be tested for haemolysis and helmet cells. An early diagnosis and initiation of necessary therapy are determining for the clinical outcome.

Von Willebrand factor (VWF) is an adhesive, multi-functional huge multimerized protein with multiple domains harboring binding sites for collagen, platelet glycoprotein receptors and coagulation factor VIII (FVIII). The functional domains enable VWF to bind to the injured vessel wall, to recruit platelets to the site of injury by adhesion and aggregation and to bind and protect FVIII, an important cofactor of the coagulation cascade. VWF function in primary haemostasis is located in particular in the arterial and micro-circulation. This environment is exposed to high shear forces with hydrodynamic shear rates ranging over several orders of magnitude from 10⁻¹ to 10⁵ s-1 and requires particular mechanisms to enable platelet adhesion and aggregation under these variable conditions. The respective VWF function is strictly correlating with its multimer size. Lack or reduction of large VWF multimers is seen in patients with von Willebrand disease (VWD) type 2A which correlates with reduction of both VWF:platelet GPIb-binding and VWF:collagen binding and a bleeding phenotype. To prevent unlimited platelet adhesion and aggregation which is the cause of the microangiopathic disorder thrombotic thrombocytopenic purpura (TTP), VWF function is regulated by its specific protease ADAMTS13. Whereas a particular susceptibility of VWF to ADAMTS13 proteolysis is the cause of a frequent VWD type 2A phenotype, lack or dysfunction of ADAMTS13, either acquired by ADAMTS13 antibodies or by inherited ADAMTS13 deficiency (Upshaw-Schulman Syndrome), causes TTP. Therefore VWD and TTP represent the opposite manifestations of VWF related disorders, tightly linked to each other.

Thrombotic-thrombocytopenic purpura (TTP) is a microangiopathic disorder characterized by multiple von Willebrand-Factor (vWF) rich microthrombi affecting the arterioles and capillary vessels of several organs. Ultra large von Willebrand multimers cause the blood clotting process by linking to platelets due to a lack of a plasma metalloprotease named ADAMTS13. Deficiency of this vWF-cleaving enzyme is caused by an inborn mutation in the gene coding or, more often, by acquired autoantibodies that inhibit ADAMTS13. TTP is a life-threatening disease which requires urgent admission to a hematological centre. Plasmapheresis therapy should be started immediately when diagnosis of primary TTP is likely. Patients typically present with schistozytes, hemolysis, thrombocytopenia and neurological abnormalities such as headache, focal deficits or coma. The monoclonal CD20 antibody rituximab targets ADAMTS13 antibody production and has the potential to be an effective therapy for relapsed TTP or initial treatment to shorten duration of plasma exchange.

Thrombotic thrombocytopenic purpura (TTP) is a severe disease with microthrombi in various organs. The idopathic subtype is characterized by reduced ADAMTS13 activity mediated via autoantibodies against this protease. Induction of autoantibodies mechanistically is incompletely understood, but certain drugs can induce anti-ADAMTS13 antibodies through hapten mechanisms.A 56-year-old man was admitted from an external hospital because of a rapidly worsening general condition, hemolytic anemia (hemoglobin 4.17 mmol/l, hematocrit 0.19), and thrombocytopenia (22 Gpt/l) for unknown reasons. Additionally, he was found to have an elevated lactate dehydrogenase (45.37 μmol/l/s). 13 days before hospitalization he had received vaccination against H1N1. Laboratory tests revealed an increased total bilirubin (126 μmol/l), and a decreased haptoglobin level (0.08 g/l). The blood smear showed 24% fragmentocytes. Direct and indirect Coombs test were negative. TPP was diagnosed based on the clinical presentation and the detection of ADAMTS13 antibodies. Despite daily plasma exchange via plasmapheresis and administration of corticosteroids, there was no significant rise in platelet counts. Immunosuppression with a total of four weekly doses of rituximab (375 mg/m(2) body surface area) was added. Over the next 5 weeks, the platelet count very slowly rose. After a total of 46 sessions, plasmapheresis was ended with complete remission of the disease.This report emphasizes the immunologic susceptibility of TTP, and suggests the potential, but not proven role of H1N1 vaccination in the pathogenesis of TTP, because no serum before vaccination was available. Severe autoantibody TTP can be successfully treated by administering rituximab in addition to standard treatment with plasmapheresis and corticosteroids.

Thrombotic microangiopathies are characterized by platelet activation, endothelial damage, hemolysis and microvascular occlusion. This group of diseases is primary represented by thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Patients present with microangiopathic hemolytic anemia and thrombocytopenia as well as occlusion-related organ ischemia to a variable degree. A deficiency of the metalloprotease ADAMTS-13 is a major risk for acute disease manifestation as this is a regulator of unusually large von Willebrand factor (vWF) multimers, which are extremely adhesive and secreted by endothelial cells. In classical TTP an ADAMTS-13 activity below 5% is specific, whereas in other forms of thrombotic microangiopathies activity of ADAMTS-13 ranges from very low to normal. Symptoms of different forms of thrombotic microangiopathy are frequently overlapping and a clear classification according to clinical criteria is often difficult. Due to a high mortality, particularly of TTP, immediate diagnosis and therapy are essential. In this article two cases of thombotic microangiopathy after cardiac surgery are reported. After exclusion of TTP and HUS as well as other etiologies of thrombotic microangiopathy a relationship between the use of extracorporeal circulation and the pathogenesis of thrombotic microangiopathy is assumed.

A 26-year-old woman was admitted from another hospital because of an increased serum creatinine (170 micromol/l). She was found to have a thrombocytopenia (14Gpt/l, WHO grade IV) with anaemia and a raised lactate dehydrogenase (25.45 micromol/l). The patient was in a reduced general state when admitted to this hospital. Her mucosal membranes were pale and she had moderate scleral icterus. During the first few hours she became clearly less alert but without motor or sensory deficits.Laboratory tests showed an increased total bilirubin (73 micromol, decreased haptoglobin (0.08 g/l), free hemoglobin was raised (20.7 micromol/l) and the blood smear showed 5.5% fragmentocytes. Direct and indirect Coombs tests were negative.Thrombotic thrombocytic purpura (TTP) was diagnosed. Daily plasmapheresis with fresh plasma replacement and administration of corticosteroids was initiated. ADAMTS13 activity (reported later) was2 % and antibodies against this protease were demonstrated. After initial improvement a motor and sensory aphasia occurred. Because of progressive thrombocytopenia, immunosuppression with a total of four doses of 375 mg/m(2)/bsa rituximab was undertaken (640 mg each), every seven days. Over the next two to three weeks the platelet count very slowly rose. The plasmapheresis was ended after a total of 65 sessions. Nine months after the last plasmapheresis the platelet count and renal functions were normal.Severe autoantibody TTP can be successfully treated by administering rituximanb, an anti-CD20 antibody, in addition to the standard treatment with plasmapheresis.

A 15-year-old female patient with TTP was admitted to our hospital for further evaluation after the initial treatment with IVIG and prednisone failed. With the detection of anti-ADAMTS13 antibodies the acquired form of TTP could be diagnosed. Despite of therapeutic plasma exchange and high dose steroids no sustained remission could be achieved. However, application of rituximab led to a normalisation of platelet counts within one week allowing the termination of plasma exchanges and reduction of oral steroids. No side effects of rituximab were observed and the patient remained in clinical remission during the following months.

Thrombotic thrombocytopenic purpura (TTP) represents a rare complication mainly in the second trimester and can, in its early stage, mimic HELLP syndrome. At 38 weeks of gestation, a 40-year-old primigravida with elevated blood pressure, thrombocytopenia and elevated liver enzymes was diagnosed with HELLP syndrome. Despite a Ceasarean section her laboratory parameters remained pathological with severe thrombocytopenia and hemolysis. In addition, the patient developed neurological comatose-like symptoms. The diagnosis of TTP was made after further tests revealed fragmented red cells in the blood, autoantibodies against ADAMTS13 and a nearly total loss of ADAMST13 plasma activity. The patient fully recovered following repeated plasmapheresis and plasma substitution as well as systemic treatment with dexamethasone. If laboratory parameters do not normalise promptly in spite of the correct treatment for an assumed HELLP syndrome, TTP may be the underlying pathology. As rapid assays for antibodies against ADAMTS13 are not available yet, special consideration must be given to the clinical details in order to make a correct diagnosis.

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy. Besides anemia and thrombocytopenia, neurological impairment is common in TTP. A 42-year-old woman was admitted to a department of obstetrics/gynecology because of severe vaginal bleeding due to thrombocytopenia. After platelet transfusion, the patient developed a reduced level of consciousness, confusion, headache, and fever. CT scan did not show pathological changes. Transcranial Doppler sonography revealed increased blood flow velocities of all basal cerebral arteries. Because encephalitis was suspected the patient was transferred to the neurological department. CSF and cerebral magnetic resonance imaging studies were normal. Finally, the detection of schistocytes in the peripheral blood smear and the strong elevation of LDH led to the diagnosis of TTP. After plasma exchange over 3 consecutive days the patient achieved complete remission. The diagnosis was confirmed by laboratory tests (activity of ADAMTS135%, IgG antibodies against ADAMTS13). Platelet transfusion may adversely affect the outcome of patients with suspected TTP. Severely deficient activity of the von Willebrand factor cleaving protease (ADAMTS13) is specific for thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a micro-angiopathic disease due to deficiency of the specific VWF cleaving protease (VWF-CP) ADAMTS13. The acquired form is caused by autoantibodies against VWF-CP, whereas mutations of the ADAMTS13 gene are responsible for inherited TTP. In childhood both forms exist with predominance of inherited TTP. The phenotype of TTP in childhood can be rather variable. Besides the classical clinical picture, abortive forms may occur that can delay the identification of patients at risk. The patients are frequently assumed to suffer from idiopathic thrombocytopenia (ITP) or Evans syndrome. Further efforts are necessary to accelerate correct diagnosis and to establish a risk-adapted prophylactic therapy.

As hallmark of TTP, generalized hyaline thrombi in the patient's microcirculation is known. These thrombi are composed of platelets and VWF. A severe defect of the VWF cleaving protease (VWF-CP) was found in all known patients with the inherited form of TTP. In contrary, although a severe deficiency of VWF-CP is specific for the acquired form, too, only a fraction of these patients is characterized by a severe deficiency. In most patients with a severe deficiency autoantibodies directed against VWF-CP is detectable in plasma. However, many patients with acquired TTP do not show any severe deficiency. Because treatment differs in inherited and acquired forms and as persistance of autoantibodies during clinical remission is of prognostic value, the determination of the activity of VWF-CP and of antibodies against VWF-CP are important parts in the workup of patients with TTP. In all methods for the determination of the activity of VWF-CP the first step is proteolysis of a specific substrate for the protease. In the second step the activity of the protease is measured by analysis of the residual VWF multimers, by the generation of specific fragments, by using the residual VWF:CB or VWF:RCo as marker of the loss of multimers or with help of specific monoclonal antibodies. In less than 30 min the cone and plate(let) aggregometer helps to distinguish between different forms of thrombotic microangiopathies. While adhesion and aggregation of platelets from a healthy person are clearly enhanced after addition of a small amount of plasma from a TTP patient, both characteristics are weakened by plasma from patients with other forms of thrombotic microangiopathy (dilution effect). Molecular genetics are established methods in the differentiation between inherited and acquired forms of TTP in those cases without autoantibodies against VWF-CP.

An 18-year old woman with a systemic lupus erythematosus was referred to our hospital with anaemia, thrombocytopenia and neurological symptoms. Skin haemorrhages had occurred some weeks before. The patient also noticed cardiac palpitations. After the primary care doctor had increased the dosage of prednisolone from 7.5 mg per day to 20 mg per day the symptoms didn't substantially change and that the patient was referred to hospital. An acute lupus flare was assumed.Laboratory examinations showed a Coombs-negative haemolytic anaemia with schistocytes. Von Willebrand factor(vWF)-cleaving protease was decreased. The presence of an inhibitor of the enzyme was proved. Further test results as anti-ds-DNA, anti-Sm, C 3, ESR, CRP were normal. C 4 was slightly decreased. Cerebral MRI, cerebral SPECT and Duplex sonography of the extracranial arteries didn't show any pathologic findings. The performed MRI of the heart revealed signs of myocardial damage.As cause of the recent symptoms a thrombotic-thrombocytopenic purpura (TTP) was diagnosed. This obviously was due to an auto-antibody against the vWF-cleaving protease. After intensive immunosuppressive therapy with prednisolone and cyclosporin the clinical and laboratory findings normalised. An acute therapy with fresh frozen plasma and plasmapheresis was not necessary, as the symptoms were moderate. Because of the transient cerebral deficits for a short time we administered a low dose of aspirin. The MRI signs of myocardial affection didn't change after 3 months of immunosuppressive treatment so that we started an ACE inhibitor treatment.Thrombocytopenia in systemic lupus erythematosus demands an individual differential diagnosis. Rare causes as TTP have to be excluded. This disorder has to be diagnosed quickly and the adequate therapy has to be started early.